Better Understanding of the Neuroprotective Mechanisms of Korean Ginseng in Stroke It has been postulated that the determinants of neuronal cell death in acute and chronic neurodegenerative conditions are mediated by free radical damage. Ginseng has been reported to be neuroprotective and a potential preventive medicine, but the underlying cellular mechanisms are still unclear. Our preliminary results prompted us to focus our attention on Korean Ginseng and test the hypothesis that the transcriptional factor Nrf2 could participate in the overall Ginseng's neuroprotective function. HO, which cleaves heme (a prooxidant) to form biliverdin/bilirubin (antioxidants), carbon monoxide (a vasodilator), and iron (a prooxidant) has been shown to play a protective role in oxidative stress, ischemia, inflammation, and hypertension. Although HO2 is constitutively expressed, HO1 is inducible. Consequently, a possible way to increase HO levels to achieve neuroprotection may be to induce HO1. Of the compounds tested in our preliminary experiments in primary neuronal cultures, Ginseng was one of the most potent HO1 inducers. Our results also indicate that pretreatment of neurons with Ginseng is sufficient to provide neuroprotection, suggesting that co-treatment during oxidative stress is not necessary. This neuroprotective effect was abolished by a protein synthesis inhibitor, and was greatly reduced by an HO inhibitor. These preliminary results implied that specific induction of HO1 could be a mechanism by which Ginseng exerts its preventive neuroprotective actions and motivated us to propose that some of the neuroprotective effects attributed to Ginseng could be mediated through HO1 induction and the associated beneficial actions of heme degradation. Recently, we and others have described Nrf2 has as a key regulator of inflammation and redox homeostasis. In Aim 1, we will determine anatomical and behavioral outcomes following ischemia in wild type mice pre-treated (acutely or chronically) with Ginseng, determine whether the beneficial effect is sustained with aging, and test whether these effects are attenuated in Nrf2 knockout mice. In Aim 2, we will determine whether Ginseng induced characteristic changes in brain cells, and start addressing in which cell types these Nrf2 changes occurs. Together, these in vivo results will help us determine whether oral consumption of a standardized Ginseng extract could be beneficial, and which cells can be most associated with the Ginseng preventive brain mechanistic pathways by which Ginseng would provide the cell/brain with resistance to acute debilitating neurodegenerative conditions. PUBLIC HEALTH RELEVANCE: For centuries, Ginseng has been reported as preventive medicine to strengthen the nervous system, but the underlying cellular mechanisms are still unclear. Our preliminary results prompted us to focus our attention on Korean Ginseng and test the hypothesis that the transcriptional factor Nrf2 could participate in Ginseng's brain protective function. Using optimized pre-clinical in vivo models, we will determine whether Ginseng can prevent brain damage and neurological decline following focal ischemia and associated with aging, thus providing a better understanding the Nrf2-mediated cytoprotective effect of Ginseng. Together, this in vivo work will assess the unique properties that Ginseng could provide the brain/cells with resistance against acute and potentially chronic debilitating neurodegenerative conditions.